The invention relates, as novel and useful industrial products, to triaromatic compounds which are vitamin D analogues. The invention also relates to a process for preparing them and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
The compounds according to the invention have pronounced activity in the fields of cell proliferation and differentiation and find applications more particularly in the topical and systemic treatment of dermatological (or other) complaints associated with a keratinization disorder, complaints with an inflammatory and/or immunoallergic component and hyperproliferation of tissues of ectodermal origin (skin, epithelium, etc.), whether benign or malignant. These compounds can also be used to combat ageing of the skin, whether light-induced or chronological, and to treat cicatrization disorders.
The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
Vitamin D is an essential vitamin for preventing and treating mineralization defects of cartilage (rickets) and of bone (osteomalacia), and even of certain forms of osteoporosis in elderly people. However, it is now accepted that its functions extend well beyond regulating bone metabolism and calcium homeostasis. Among these functions, mention may be made of its actions on cell proliferation and differentiation and the control of the immune defences. Their discovery has opened the way to novel therapeutic approaches in dermatology, carcinology and in the field of autoimmune diseases and that of organ or tissue transplants.
An efficient therapeutic supply has long been confounded by the toxicity of this vitamin (occasionally fatal hypercalcaemia). Structural analogues of vitamin D are currently synthesized, some of which conserve only the differentiating properties and have no action on calcium metabolism.
One of the aims of the present invention is to propose novel compounds which are structural analogues of vitamin D and which show selective activity on cell proliferation and differentiation without displaying any hypercalcaemiant nature.
Another aim of the present invention is to propose novel compounds which are analogues of vitamin D and which are more readily synthesized and thus more economical than those known previously.
Thus, the present invention relates to compounds which can be represented by the general formula (I) below: 
in which:
R1 represents a hydrogen atom, a CH3 radical or a radical xe2x80x94(CH2)rxe2x80x94OR4,
R2 represents a radical xe2x80x94(CH2)sxe2x80x94OR5 
r, s, R4 and R5 having the meanings given below,
Xxe2x80x94Y represents a bond chosen from the bonds of formulae (a) to (d) below which can be read from left to right or vice-versa: 
R6 and W having the meanings given below,
Ar1 represents a ring of formulae (e) to (i) below: 
R7, R8 and R9 having the meanings given below,
Ar2 represents a ring of formulae (j) to (n) below: 
R10, R11 and R12 having the meanings given below,
R3 represents a radical of formula: 
t, R13, R14 and R15 having the meanings given below,
r and s, which may be identical or different, being 1 or 2,
R4 and R5, which may be identical or different, represent a hydrogen atom, an acetyl radical, a benzoyl radical, a trimethylsilyl radical, a tert-butyldimethylsilyl radical or a tetrahydropyranyl radical,
R6 represents a hydrogen atom or a lower alkyl radical,
W represents an oxygen or sulphur atom, a CH2 radical or an NH radical which can be substituted with a lower alkyl radical,
R7 and R10, which may be identical or different, represent a hydrogen atom or a lower alkyl radical,
R8, R9, R11 and R12, which may be identical or different, represent a hydrogen atom, a lower alkyl radical, a halogen atom, a radical xe2x80x94OR16, a polyether radical, a CF3 radical, an NO2 radical or an amino radical which may be substituted with one or two lower alkyl radicals,
R16 having the meanings given below,
t being 0 or 1,
R13 and R14, which may be identical or different, represent a hydrogen atom, a lower alkyl radical, a cycloalkyl radical, a CF3 radical or a C2F5 radical,
R15 represents a hydrogen atom, an acetyl radical, a trimethylsilyl radical, a tert-butyldimethylsilyl radical or a tetrahydropyranyl radical,
R16 represents a hydrogen atom or a lower alkyl radical.
The invention is also directed towards the optical and geometrical isomers of the said compounds of formula (I) as well as to the salts thereof when Xxe2x80x94Y represent a bond of formula (a) and W represents an xe2x80x94NHxe2x80x94 radical optionally substituted with a lower alkyl radical.
When the compounds according to the invention are in the form of salts, they are pharmaceutically or cosmetically acceptable salts obtained by addition of an inorganic or organic acid, in particular hydrochloric acid, sulphuric acid, acetic acid, fumaric acid, hemisuccinic acid, maleic acid or mandelic acid.
According to the present invention, the expression xe2x80x9clower alkyl radicalxe2x80x9d means a linear or branched radical containing from 1 to 6 carbon atoms, and preferably methyl, ethyl, isopropyl, tert-butyl and hexyl radicals.
The expression xe2x80x9ccycloalkyl radicalxe2x80x9d means a cyclic alkane radical containing from 3 to 6 carbon atoms. The cycloalkyl radical is preferably chosen from a cyclopropyl, cyclopentyl or cyclohexyl radical.
The expression xe2x80x9chalogen atomxe2x80x9d preferably means a fluorine, chlorine or bromine atom.
The expression xe2x80x9cpolyether radicalxe2x80x9d means a radical containing from 2 to 5 carbon atoms interrupted with at least two oxygen atoms, such as methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.
Among the compounds of formula (I) falling within the context of the present invention, mention may be made in particular of the following:
{5-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-5-[4xe2x80x2-(1-hydroxy-1-methylethyl)biphenyl-3-yloxymethyl]phenyl}methanol
{5-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2xe2x80x2-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-5-[4xe2x80x2-(1-hydroxy-1-methylethyl)-2xe2x80x2-methylbiphenyl-3-yloxymethyl]phenyl}methanol
(5-{2-[3xe2x80x2-(1-ethyl-1-hydroxypropyl)biphenyl-3-yl]ethyl)-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-5-[3xe2x80x2-(1-hydroxy-1-methylethyl)-biphenyl-3-yloxymethyl]phenyl}methanol
{5-[4xe2x80x2-(2-ethyl-2-hydroxybutyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{5-[3xe2x80x2-(2-ethyl-2-hydroxybutyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
1-[3xe2x80x2-(3,4-bis-hydroxymethyl-benzyloxy)biphenyl-3-yl]-2-methyl-2-propanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2xe2x80x2-methylbiphenyl-3-ylsulphanylmethyl]-2-hydroxymethylphenyl}methanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2,2-dimethylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-4-[4xe2x80x2-(1-hydroxy-1-propylbutyl)-2,2-dimethylbiphenyl-3-yloxymethyl]phenyl}methanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2,2xe2x80x2,6xe2x80x2-trimethylbiphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl}methanol
(4-{3-[5-(1-ethyl-1-hydroxypropyl)-2-pyridyl]phenoxymethyl}-2-hydroxymethylphenyl)methanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6,2xe2x80x2-dimethylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6,2xe2x80x2,6xe2x80x2-trimethylbiphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl}methanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2xe2x80x2,6xe2x80x2-dimethylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
1-{4-[3-(3,4-bis-hydroxymethyl-benzyloxy)phenyl]-2-thienyl}-1-propanol
(4-{3-[4-(1-ethyl-1-hydroxypropyl)-2-thienyl]phenoxymethyl}-2-hydroxymethylphenyl)methanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2xe2x80x2-methylbiphenyl-3-ylmethoxy]-2-hydroxymethylphenyl}methanol
1-[3xe2x80x2-(3,4-bis-hydroxymethyl-phenoxymethyl)-2-methylbiphenyl-4-yl]-1-propanol
{4-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-3xe2x80x2-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{5-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2xe2x80x2-methylbiphenyl-4-yloxymethyl]-2-hydroxymethylphenyl}methanol
{4-[2xe2x80x2-tert-butyl-4xe2x80x2-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
1-[3xe2x80x2-(3,4-bis-hydroxymethyl-benzyloxy)-2-methyl-biphenyl-4-yl[-2,2-dimethyl-1-propanol
1-[3xe2x80x2-(3,4-bis-hydroxymethyl-benzyloxy)-2-methylbiphenyl-4-yl]-2-methyl-1-propanol
{2-hydroxymethyl-4-[methyl(trifluorohydroxytrifluoromethylethyl)biphenyl-3-yloxymethyl]phenyl}methanol
[5-(2-{5-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-2-thienyl}ethyl)-2-hydroxymethylphenyl)methanol
(5-{5xe2x80x2-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-2-thienylmethoxy}-2-hydroxymethylphenyl)methanol
[5-(2-{5-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]-2-thienyl}ethyl)-2-hydroxymethylphenyl]methanol
(5-{5-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]-2-thienylmethoxy}-2-hydroxymethylphenyl)methanol
[5-(2-{5-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-4-methyl-2-thienyl}ethyl)-2-hydroxymethylphenyl]-methanol
(5-{5-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-4-methyl-2-thienylmethoxy}-2-hydroxymethylphenyl)methanol
[2-hydroxymethyl-5-{2-[5-[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-2-thienyl}ethyl)phenyl]-methanol
(2-hydroxymethyl-5-{5-[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-2-thienylmethoxy}phenyl)-methanol
[5-(2-{5-[ethyl(trifluorohydroxytrifluoromethylethyl)-phenyl]-2-thienyl}ethyl)-2-hydroxymethylphenyl]methanol
(5-{5-[ethyl(trifluorohydroxytrifluoromethylethyl)-phenyl]-2-thienylmethoxy}-2-hydroxymethylphenyl)-methanol
[2-hydroxymethyl-5-(2-{methyl[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-2-thienyl}ethyl)phenyl]-methanol
{2-hydroxymethyl-5-(methyl[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-2-thienylmethoxy}phenyl)-methanol
[5-(2-{5-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-3-thienyl}ethyl)-2-hydroxymethylphenyl]methanol
(5-{5-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-3-thienylmethoxy}-2-hydroxymethylphenyl)methanol
[5-(2-{5-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]-3-thienyl}ethyl)-2-hydroxymethylphenyl]methanol
(5-{5-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]-3-thienylmethoxy}-2-hydroxymethylphenyl)methanol
[2-hydroxymethyl-5-(2-{5-[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-3-thienyl}ethyl)phenyl]-methanol
(2-hydroxymethyl-5-{5-[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-3-thienylmethoxy}phenyl)-methanol
[5-(2-{5-[ethyl(trifluorohydroxytrifluoromethylethyl)-phenyl]-3-thienyl}ethyl)-2-hydroxymethylphenyl]methanol
(5-{5-[ethyl(trifluorohydroxytrifluoromethylethyl)-phenyl]-3-thienylmethoxy}-2-hydroxymethylphenyl)-methanol
[5-(2-{4-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-2-thienyl}ethyl)-2-hydroxymethylphenyl]methanol
(5-{4-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-2-thienylmethoxy}-2-hydroxymethylphenyl)methanol
[5-(2-{4-[2-ethyl4-(1-ethyl-1-hydroxypropyl)phenyl]-2-thienyl}ethyl)-2-hydroxymethylphenyl]methanol
(5-{4-[2-ethyl-4-(1-ethyl-1-hydroxypropyl)phenyl]-2-thienylmethoxy}-2-hydroxymethylphenyl)methanol
[5-(2-{4-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-5-methyl-2-thienyl}-ethyl)-2-hydroxymethylphenyl]-methanol
(5-{4-[4-(1-ethyl-1-hydroxypropyl)-2-methylphenyl]-5-methyl-2-thienylmethoxy}-2-hydroxymethylphenyl)methanol
[2-hydroxymethyl-5-(2-{4-[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-2-thienyl}ethyl)phenyl]-methanol
(2-hydroxymethyl-5-{4-[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-2-thienylmethoxy}phenyl]-methanol
[5-(2-(4-[ethyl(trifluorohydroxytrifluoromethylethyl)-phenyl]-2-thienyl}ethyl)-2-hydroxymethylphenyl]methanol
(5-{4-[ethyl(trifluorohydroxytrifluoromethylethyl)-phenyl]-2-thienylmethoxy}-2-hydroxymethylphenyl)-methanol
[2-hydroxymethyl-5-(2-{methyl[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-2-thienyl}ethyl)phenyl]-methanol
(2-hydroxymethyl-5-{methyl[methyl(trifluorohydroxytrifluoromethylethyl)phenyl]-2-thienylmethoxy}phenyl)-methanol
{5-[2xe2x80x2-ethyl-4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}-methanol
{5-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2xe2x80x2-isopropyl-6-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}-methanol
{5-[2xe2x80x2-tert-butyl-4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}-methanol
{5-[ethylmethyl(trifluorohydroxytrifluoromethylethyl)-biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-5-[2xe2x80x2-isopropyl-6-methyl-4xe2x80x2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)biphenyl-3-yloxymethyl]phenyl}methanol
{5-[dimethylethylmethyl(trifluorohydroxytrifluoromethylethyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{5-[6-ethyl-4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2xe2x80x2-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{5-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6-methoxy-2xe2x80x2-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{5-[6-tert-butyl-4xe2x80x2-(1-ethyl-1-hydroxypropyl)-2xe2x80x2-methylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}-methanol
{5-[ethylmethyl(trifluorohydroxytrifluoromethylethyl)-biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol
{2-hydroxymethyl-5-[6-methoxy-2xe2x80x2-methyl-4xe2x80x2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)biphenyl-3-yloxymethyl]phenyl}methanol
{5-[dimethylethylmethyl(trifluorohydroxytrifluoromethylethyl)biphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl}methanol
(5-{2-[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6,2xe2x80x2-dimethylbiphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)-methanol
(5-{2-[dimethyl(trifluorohydroxytrifluoromethylethyl)-biphenyl-3-yl]ethyl}-2-hydroxymethylphenyl)methanol
(5-{[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6,2xe2x80x2-dimethylbiphenyl-3-ylamino]methyl}-2-hydroxymethyl-phenyl)methanol
(5-{[dimethyl(trifluorohydroxytrifluoromethylethyl)-biphenyl-3-ylamino]methyl}-2-hydroxymethylphenyl)-methanol
[5-({[4xe2x80x2-(1-ethyl-1-hydroxypropyl)-6,2xe2x80x2-dimethylbiphenyl-3-yl]methylamino}methyl)-2-hydroxymethylphenyl]-methanol
[5-({[dimethyl(trifluorohydroxytrifluoromethylethyl)-biphenyl-3-yl]methylamino}methyl)-2-hydroxymethyl-phenyl]methanol
According to the present invention, the compounds of formula (I) which are more particularly preferred are those for which at least one, and preferably all, of the conditions below are satisfied:
R1 represents a CH3 or CH2OH radical,
R2 represents a CH2OH radical,
Xxe2x80x94Y represents a bond of formula (a) or (c),
R3 represents the radical C(R13) (R14)OH.
A subject of the present invention is also processes for preparing the compounds of formula (I).
FIGS. 1 to 5 represent reaction schemes which can be used to prepare the compounds according to the invention.
Thus, the compounds of formula I(a) can be obtained (FIG. 1) by reacting a halo compound, preferably a bromo compound (1) with a phenolic (Yxe2x95x90OH), thiophenolic (Yxe2x95x90SH) or aniline (Yxe2x95x90NHxe2x80x94COO-tert-butyl) derivative (3) in the presence of a base such as K2CO3 in a solvent such as acetone or methyl ethyl ketone.
The compounds of formula I(a) can also be obtained (FIG. 1) by reacting a halo compound, preferably a bromo compound (1) with the sodium or potassium salt of a phenolic (Yxe2x95x90OH), thiophenolic (Yxe2x95x90SH) or aniline (Yxe2x95x90NHxe2x80x94COO-tert-butyl) derivative (3) in a solvent such as dimethylformamide (DMF).
The compounds of formula I(b) can be obtained (FIG. 1) by reacting a benzoic derivative (2) with a phenolic (Yxe2x95x90OH), thiophenolic (Yxe2x95x90SH) or aniline (Yxe2x95x90NH2) derivative (3) in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide in a solvent such as dichloromethane or tetrahydrofuran (THF).
The compounds of formula I(b) can also be obtained (FIG. 1) by reacting a benzoyl chloride (obtained by reacting a benzoic derivative (2) with thionyl chloride or oxalyl chloride) with a phenolic (Yxe2x95x90OH), thiophenolic (Yxe2x95x90SH) or aniline (Yxe2x95x90NH2) derivative (3) in the presence of a base such as triethylamine in a solvent such as dichloromethane or tetrahydrofuran (THF).
The compounds (1), (2) and (3) can be obtained according to the reaction schemes presented in FIGS. 2, 3 and 4. The methods for preparing the compounds (1) and (2) have the advantage of limiting the number of preparation steps.
In FIG. 2, (a) represents a reaction with BH3 in dioxane, (b) represents a reaction with CH3OCH2Cl in the presence of sodium hydride in a dimethylformamide solvent, (c) represents a reaction with n-butyllithium in the presence of CO2 in tetrahydrofuran, (d) represents a reaction with n-butyllithium in tetrahydrofuran followed by a reaction with dimethylformamide, (e) represents a reduction reaction with sodium borohydride in a methanol-tetrahydrofuran solvent and (f) represents a reaction with carbon tetrabromide in the presence of triphenylphosphine in a dichloromethane solvent.
In FIG. 3, (a) represents a reaction with BH3 in dioxane, (b) represents a reaction with methanol in the presence of sulphuric acid, (c) represents a reaction with t-C4H9(CH3)2SiCl in the presence of imidazole in a dimethylformamide solvent, (d) represents a reaction with LiAlH4 in ether, (e) represents a reaction with benzoyl chloride in the presence of triethylamine in tetrahydrofuran, (f) represents a reaction with (C4H9)4NF in tetrahydrofuran and (g) represents a reaction with carbon tetrabromide in the presence of triphenylphosphine in a dichloromethane solvent.
The derivatives (3) can be obtained according to the reaction scheme indicated in FIG. 4. A Suzuki-type reaction between a boronic derivative (4) and an iodoaryl derivative (5) in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium gives the ester derivative (6) which is converted into the derivative (3) by reaction with an alkylmagnesium or cycloalkylmagnesium halide or an alkyllithium.
The compounds of formula I(c) can be obtained (FIG. 5) by a Horner-Emmons reaction between the phosphonate derivative (8) (obtained from the corresponding benzyl bromide by an Arbuzov reaction) and the benzaldehyde (7).
The compounds of formula I(d) can be obtained from the compounds I(c) by hydrogenation of the double bond in the presence of palladium-on-charcoal.
The compounds of formula I(e) can also be obtained (FIG. 6) by a Sonogashira reaction between an acetylenic derivative (9) (obtained by reacting the benzaldehyde (7) by a Corey-Fuchs reaction) and a triflate derivative (Xxe2x95x90OSO2CF3) or iodo derivative (Xxe2x95x90I) (10) in the presence of a transition metal catalyst such as Pd(Cl)2(PPh3)2 and CuI in a solvent such as triethylamine.
The compounds of general formula (1) have biological properties analogous to those of vitamin D, in particular the properties of transactivation of the vitamin D response elements (VDRE), such as an agonist or antagonist activity with respect to receptors of vitamin D or derivatives thereof. The expression xe2x80x9cD vitamins or derivatives thereofxe2x80x9d means, for example, the derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3 (calcitriol).
This agonist activity with respect to receptors of vitamin D or derivatives thereof can be demonstrated xe2x80x9cin vitroxe2x80x9d by methods known in the field of study of gene transcription (Hansen et al., The Society for Investigative Dermatologie, vol. 1, No. 1, April 1996).
By way of example, the VDR agonist activity can be tested on the HeLa cell line by co-transfection with an expression vector for the human VDR receptor and the reporter plasmid p240Hase-CAT which contains the region xe2x88x921399 to +76 of rat 24-hydroxylase promoter, cloned upstream of the frame encoding the chloramphenicol-acetyl-transferase (CAT)xe2x80x2gene. 18 hours after co-transfection, the test product is added to the medium. 18 hours after treatment, assay of the CAT activity in the cell lysates is carried out by an ELISA test. The results are expressed as percentages of the effect normally observed with 10xe2x88x927M calcitriol.
The agonist activity can also be characterized in this co-transfection system, by determining the dose required to reach 50% of the maximum activity of the product (AC50).
The biological properties of the vitamin D analogues can also be measured by the capacity of the product to inhibit the proliferation of normal human keratinocytes (NHK in culture). The product is added to NHKs cultured under conditions which promote the proliferative state. The product is left in contact with the cells for 5 days. The number of proliferative cells is measured by incorporation of bromodeoxyuridine (BRdU) into the DNA.
The vitamin D receptor agonist activity of the compounds of the invention can also be evaluated xe2x80x9cin vivoxe2x80x9d by induction of 24-hydroxylase in SKH mice. (Voorhees et al., 1997.108: 513-518).
A subject of the present invention is also, as medicinal product, the compounds of formula (I) as described above.
The compounds according to the invention are particularly suitable in the following fields of treatment:
1) for treating dermatological complaints associated with a keratinization disorder which has a bearing on differentiation and on proliferation, in particular for treating simple acne, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acne such as solar, medication-related or professional acne,
2) for treating other types of keratinization disorders, in particular ichthyosis, ichthyosiform states, Darier""s disease, palmoplantar keratoderma, leukoplasias and leukoplasiform states, and cutaneous or mucous (buccal) lichen,
3) for treating other dermatological complaints with an inflammatory immunoallergic component, with or without cell proliferation disorder, and, in particular, all forms of psoriasis, whether this is cutaneous, mucous or ungual psoriasis, and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema or respiratory atopy or alternatively gingival hypertrophy,
4) for treating all dermal or epidermal proliferations, whether benign or malignant and whether they are of viral origin or otherwise, such as common warts, flat warts and verruciform epidermodysplasia, oral or florid papillomatoses, T lymphoma and proliferations which may be induced by ultraviolet radiation, in particular in the case of basocellular and spinocellular epithelioma, as well as any pre-cancerous skin lesion such as keratoacanthomas,
5) for treating other dermatological disorders such as immune dermatitis such as lupus erythematosus, immune bullosis and collagen diseases such as scleroderma,
6) in the treatment of dermatological or general complaints with an immunological component,
7) for combating disorders of sebaceous function such as the hyperseborrhoea of acne or simple seborrhoea,
8) in the treatment of skin disorders due to exposure to UV radiation, as well as for repairing or combating ageing of the skin, whether it is light-induced or chronological ageing, or for reducing actinic keratoses and pigmentations, or any pathologies associated with chronological or actinic ageing,
9) for preventing or treating cicatrization disorders or for preventing or repairing stretchmarks,
10) in the treatment of inflammatory complaints such as arthritis,
11) in the treatment of any complaint of viral origin on the skin or generally, such as Kaposi""s syndrome,
12) for treating certain ophthalmological disorders, in particular corneopathies,
13) in the treatment or prevention of cancerous or pre-cancerous states of cancers presenting or possibly being induced by vitamin D receptors, such as, but without limitation, breast cancer, leukaemia, myelodysplasic syndromes and lymphomas, carcinomas of the Malpighian epithelial cells and gastrointestinal cancers, melanomas and osteosarcoma,
14) in the prevention or treatment of alopecia of various origins, in particular alopecia due to chemotherapy or radiation,
15) in the treatment of immune complaints, such as autoimmune diseases, for instance type 1 diabetes mellitus, multiple sclerosis, lupus and lupus-type complaints, asthma, glomerulonephritis, selective dysfunctions of the immune system such as AIDS, or prevention of immune rejection such as kidney, heart, bone marrow, liver, pancreatic islets, pancreas or skin graft rejects, or prevention of graft-versus-host disease,
16) in the treatment of endocrine complaints, given that the vitamin D analogues can modify hormonal secretion such as increasing the secretion of insulin or selectively suppressing the secretion of parathyroid hormone, for example in chronic renal insufficiency and secondary hyperparathyroidism, -p 17) in the treatment of complaints characterized by abnormal management of intracellular calcium, and in the treatment or prevention of pathologies in which calcium metabolism is involved, such as muscular ischaemia (myocardial infarction), -p 18) in the treatment or prevention of vitamin D deficiencies and other mineral homeostasis complaints in plasma and bone, such as rickets, osteomalacia, osteoporosis, in particular in the case of menopausal women, renal osteodystrophy and parathyroid function disorders,
19) in the treatment of complaints of the cardiovascular system such as arteriosclerosis or hypertension; as well as non-insulin-dependent diabetes.
In the therapeutic fields mentioned above, the compounds according to the invention can advantageously be used in combination with retinoids, with corticosteroids or oestrogens, in combination with antioxidants, with xcex1-hydroxy or xcex1-keto acids or derivatives thereof, with potassium-channel blockers, or alternatively in combination with other medicinal products known to interfere with the immune system .(for example cyclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, etc.
The term xe2x80x9cretinoidsxe2x80x9d means either natural or synthetic RAR- or RXR-receptor ligands.
The expression xe2x80x9cfree-radical scavengersxe2x80x9d means, for example, xcex1-tocopherol, superoxide dismutase, ubiquinol or certain metal-chelating agents.
The expression xe2x80x9cxcex1-hydroxy or xcex1-keto acids or derivatives thereofxe2x80x9d means, for example, lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, glyceric acid, ascorbic acid and salicylic acid derivatives, as well as salts, amides or esters thereof.
The expression xe2x80x9cpotassium-channel blockersxe2x80x9d means, for example, Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.
A subject of the present invention is also a pharmaceutical composition comprising at least one compound of formula (I) as defined above.
A subject of the present invention is thus also such a pharmaceutical composition intended in particular for treating the abovementioned complaints.
The compounds according to the invention can be administered via the enteral, parenteral, topical or occular route.
Via the enteral route, the pharmaceutical compositions can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles allowing controlled release. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection. The compounds according to the invention are generally administered at a daily dose of about from 0.001 xcexcg/kg to 1000 xcexcg/kg and preferably of about from 0.01 xcexcg/kg to 100 xcexcg/kg of bodyweight in 1 to 3 dosage intakes.
Via the topical route, the pharmaceutical compositions based on compounds according to the invention are intended for treating the skin and mucous membranes and are in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or nanospheres or lipid vesicles or polymer vesicles or polymer patches and hydrogels allowing controlled release. These topical-route compositions can be either in anhydrous form or in aqueous form depending on the clinical indication.
Via the ocular route, they are mainly eye drops.
These topical-route or ocular-route compositions contain at least one compound of formula (I) as defined above at a concentration preferably of between 0.0001% and 5% and preferably between 0.001% and 1% relative to the total weight of the composition.
The compounds of formula (I) according to the invention also find an application in the cosmetics field, in particular in body and hair hygiene and especially for treating skin with a tendency towards acne, for regrowth of the hair, for preventing hair loss, for combating the greasy appearance of the skin or the hair, in protecting against the harmful effects of sunlight or in treating physiologically dry skin, for preventing and/or combating light-induced or chronological ageing.
In the cosmetics field, the compounds according to the invention can advantageously be used in combination with retinoids, with corticosteroids, in combination with free-radical scavengers, with xcex1-hydroxy or xcex1-keto acids or derivatives thereof, or alternatively with ion-channel blockers, the various products taken in combination with the compounds of the present invention being as defined above.
The present invention is thus also directed towards a cosmetic composition containing, in a cosmetically acceptable support, at least one compound of formula I as defined above. This cosmetic composition can be in particular in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipid vesicles or polymer vesicles, a soap or a shampoo.
The concentration of compound of formula I in the cosmetic compositions can be between 0.001% and 3% by weight relative to the total weight of the composition.
The pharmaceutical and cosmetic compositions according to the invention can also contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and, in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone and derivatives thereof or urea; antiseborrhoeic or antiacne agents, such as S-carboxymethylcysteine or S-benzylcysteamine and salts and derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin, clindamycin and esters thereof, tetracyclines; antifungal agents such as ketoconazole or poly-4,5-methylene-3-isothiazolinones; agents for promoting regrowth of the hair, such as Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,4-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids, and in particular xcex2-carotene; anti-psoriatic agents such as anthralin and derivatives thereof, and, finally, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, and esters and amides thereof.
The compositions according to the invention can also contain flavour enhancers, preserving agents such as para-hydroxybenzoic acid esters, stabilizers, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifiers, UV-A and UV-B screening agents, antioxidants such as xcex1-tocopherol, butylhydroxyanisole or butylhydrodxytoluene.
Several examples of the production of active compounds of formula (I) according to the invention, and several concrete formulations based on such compounds, and an example of a test for evaluating the biological activity of compounds of formula (I) according to the invention, will now be given by way of illustration and with no limiting nature.